Large Cohort Of Long-term Survivors Research Articles

Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer

Despite advancements in cancer therapy and supportive care, childhood cancer survivors remain at risk for chronic morbidities associated with disease and treatment, such as hearing impairment (HI) and neurocognitive deficits. This study, to our knowledge, is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures. To assess the association of HI with neurocognitive function and the factors in HI that mediate neurocognitive outcomes in survivors of childhood cancer. Data analyzed in this cross-sectional study were collected for the period April 25, 2007, to June 30, 2017, from participants in the St. Jude Lifetime Cohort Study (SJLIFE), an ongoing study that quantifies the long-term health outcomes of survivors of childhood cancer. Participants included those treated at St. Jude Children's Research Hospital (Memphis, Tennessee) for childhood cancer who survived 5 or more years after their original diagnosis and who were eligible for audiologic and neurocognitive testing. Hearing outcomes were coded using the Chang Ototoxicity Grading Scale. Data analysis was performed from March 22, 2019, to March 5, 2020. Hearing and neurocognitive function. Survivors were grouped by hearing sensitivity (normal hearing [Chang grade 0], mild HI [Chang grades 1a, 1b, and 2a], or severe HI [Chang grade ≥2b]) and stratified by treatment exposure (platinum-only exposure group [treated with cisplatin and/or carboplatin chemotherapy], cochlear radiotherapy [RT] exposure group [treated with cochlear RT with or without platinum-based chemotherapy], or no exposure group [no platinum-based chemotherapy or cochlear RT]). Multivariable log-binomial models were adjusted for age at diagnosis, time since diagnosis, sex, and relevant treatment exposures. A total of 1520 survivors of childhood cancer were analyzed, among whom 814 were male survivors (53.6%), the median (interquartile range [IQR]) age was 29.4 (7.4-64.7) years, and the median (IQR) time since diagnosis was 20.4 (6.1-53.8) years. Prevalence and risk of severe HI among survivors were higher in survivors in the platinum-only (n = 107 [34.9%]; relative risk [RR], 1.68 [95% CI, 1.20-2.37]) or cochlear RT (n = 181 [38.3%]; RR, 2.69 [95% CI, 2.02-3.57) exposure group compared with those in the no exposure group (n = 65 [8.8%]). Severe HI was associated with deficits in verbal reasoning skills (no exposure group RR, 1.11 [95% CI, 0.50-2.43]; platinum-only exposure group RR, 1.93 [95% CI, 1.21-3.08]; cochlear RT exposure group RR, 2.00 [95% CI, 1.46-2.75]), verbal fluency (no exposure group RR, 1.86 [95% CI, 1.19-2.91]; platinum-only exposure group RR, 1.83 [95% CI, 1.24-2.71]; cochlear RT exposure group RR, 1.45 [95% CI, 1.09-1.94]), visuomotor speed (no exposure group RR, 1.87 [95% CI, 1.07-3.25]; platinum-only exposure group RR, 3.10 [95% CI, 1.92-4.99]; cochlear RT exposure group RR, 1.40 [95% CI, 1.11-1.78]), and mathematics skills (no exposure group RR, 1.90 [95% CI, 1.18-3.04]; platinum-only exposure group RR, 1.63 [95% CI, 1.05-2.53]; cochlear RT exposure group RR, 1.58 [95% CI, 1.15-2.18]), compared with survivors with normal hearing or with mild HI. Results of this study suggest that severe HI in childhood cancer survivors is associated with neurocognitive deficits independent of the neurotoxic treatment received. Early screening and intervention for HI may facilitate the development and maintenance of neurocognitive function and identify individuals at risk for impairment.

Longitudinal evaluation of alanine aminotransferase after treatment for childhood cancer. A report from the St. Jude Lifetime Cohort Study.

e22525 Background: Many childhood cancer survivors have been exposed to hepatotoxic agents. We assessed longitudinal hepatic injury, using alanine aminotransferase (ALT) elevation, and associated factors in a large cohort of long-term survivors. Methods: We evaluated SJLIFE participants ( > 10 years post-diagnosis, age ≥18 years) who had two or more determinations of ALT (T1 baseline, T2 last evaluation). Elevated ALT was defined as ALT > Upper Limit of Normal (ULN, 30 IU/mL for males and 19 IU/mL for females). Elastic net was used to perform model selection for elevated ALT at T2. Modified Poisson regression was used to identify risk factors for elevated ALT at T2. Results: Serial ALT assessments were available for 1941 survivors (49.6% female, 82.2% non-Hispanic white [NHW]). Their median age at diagnosis and T1 were 7.6 years (interquartile range [IQR] = 3.4-13.5) and 31.7 years (IQR = 26.1-38.1), respectively. Elapsed time from diagnosis to T1, and T1 to T2, were 23.3 years (IQR = 17.8-29.6) and 5.2 years (IQR = 4.4-5.7). ALT was normal at T1 and T2 in 45.7%, and persistently (25.9%) or newly (11.7%) abnormal in 37.6%. Compared to those with normal ALT at T1, those with elevated ALT at T2 were more likely to have NHW race/ethnicity, treatment with busulfan, increasing volume of the liver exposed to 10 Gray (Gy) or more (V10), body mass index (BMI) > 25 kg/m2, hepatitis C, metabolic syndrome, or treatment with atorvastatin, rosuvastatin or simvastatin at T2. History of hematopoietic stem cell transplantation (HSCT), but not busulfan, were additional risk factors included in the models for V15 and V20 (Table). Conclusions: Demographic, treatment, lifestyle, and non-oncologic interventions increase the risk for ALT elevation in survivors. These results may guide future treatment designs and lifestyle interventions. [Table: see text]

Genetic basis of subsequent malignant neoplasms

Subsequent malignant neoplasms (SMNs) are one of the most serious late complications in pediatric patients with cancer, with more than 10% of long-term cancer survivors developing SMNs. Germline mutations in cancer predisposition genes have been recently highlighted as a risk factor. For example, germline mutations in the TP53 gene were reported to be a risk factor for SMNs. A comprehensive genomic analysis for a large cohort of long-term survivors of childhood cancer showed that variants in cancer predisposition genes were correlated with the higher cumulative incidence of SMNs. As another genetic risk, previous reports suggested that polymorphisms in genes regulating thiopurine pathway such as TPMT gene might contribute to SMN development after acute lymphoblastic leukemia treatment. Considering improved survival probability, attention should be paid for late complications. Thus, therapeutic strategy should be optimized based on a risk for SMNs of each individual.

Surveillance of hepatic late adverse effects in a large cohort of long-term survivors of childhood cancer: Prevalence and risk factors

BackgroundChildhood cancer survivors (CCS) are a growing group of young individuals with a high risk of morbidity and mortality. We evaluated the prevalence and risk factors of hepatic late adverse effects, defined as elevated liver enzymes, in a large cohort of CCS. MethodsThe cohort consisted of all five-year CCS treated in the EKZ/AMC between 1966 and 2003, without hepatitis virus infection and history of veno-occlusive disease (VOD). Liver enzyme tests included serum levels of alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (γGT) for biliary tract injury. We performed multivariable linear and logistic regression analyses. ResultsThe study population consisted of 1404 of 1795 eligible CCS, of whom 1362 performed liver enzyme tests at a median follow-up of 12years after diagnosis. In total, 118 (8.7%) of 1362 CCS had hepatic late adverse effects defined as ALT or γGT above the upper limit of normal. Abnormal ALT and γGT levels were found in 5.8% and 5.3%, respectively. In multivariable regression analyses treatment with radiotherapy involving the liver, higher body mass index, higher alcohol intake and longer follow-up time were significantly associated with elevated ALT and γGT levels; older age at diagnosis was only significantly associated with elevated γGT levels (all p<0.05). ConclusionOne in twelve CCS showed signs of hepatic late adverse effects after a median follow-up of 12years. Several risk factors have been identified. Future studies should focus on the course of long-term liver related outcomes and on the influence of radiotherapy and chemotherapy dose.

Delayed Chronic Kidney Disease (CKD) after Hematopoietic Cell Transplantation (HCT).

Exposure to pre-transplant nephrotoxic agents, total body irradiation (TBI), and presence of chronic graft-versus-host disease (cGVHD) have been identified as risk factors for developing CKD after HCT. However, small sample size, short follow-up post-HCT, and varying definitions of CKD have precluded a precise estimation of the magnitude of risk and associated risk factors. The aim of the current study was to describe the incidence and risk factors associated with the development of delayed CKD in HCT survivors. Eligible subjects underwent HCT for hematological malignancies or severe aplastic anemia at City of Hope, survived at least one year post-transplant, and were free of CKD at one year post-HCT. Information on pre-transplant therapeutic exposures and post-transplant CKD was obtained via medical record abstraction. All CKD cases were defined according to the National Kidney Foundation's definition based on glomerular filtration rate (GFR) values. The endogenous filtration marker creatinine was used to estimate GFR values. CKD was defined as a sustained elevation of serum creatinine which infer a GFR of less than 60 mL/min/1.73 m2 for 3 months or longer. The equation used to calculate GFR was as follows: GFR = 186 x (Pcr) −1.154 x (age) − 0.203 (x 0.742 if female) (x 1.210 if African American). Totally, 1,546 eligible subjects were identified (median age at HCT of 34.4, median length of follow-up 6.2 years; autologous HCT in 718 patients [46%], related donor HCT in 726 patients [47%], and unrelated donor HCT in 102 patients [7%]; 59% of subjects (n=913) were male). A total of 65 patients were identified with CKD, resulting in a cumulative incidence of 3.6% [95% confidence interval (CI), 2.6% to 4.6%] at five years post–HCT and 4.8% at 10 years (autologous HCT: 2.9% at five years; matched sibling HCT: 4.1%; matched unrelated donor HCT: 10.5%, p<0.05). In allogeneic transplant recipients, older age at HCT (RR per increase of five years, 1.34; 95% CI, 1.30 to 1.38), prophylaxis/treatment of GvHD with cyclosporine and/or tacrolimus (RR, 4.32; 95% CI, 1.25 to 14.89), and a primary diagnosis of Multiple Myeloma (RR=5.38, 95% CI=1.79 to 16.15) were associated with increased risk. For autologous transplant recipients, older age at HCT was associated with increased risk (RR per increase of five years, 1.33; 95% CI, 1.29 to 1.38). Of note, use of TBI, and chemotherapeutic agents for conditioning, and a history of fungal infection were not associated with risk of delayed CKD development. This study describes the magnitude of risk of delayed chronic kidney disease in a large cohort of long-term survivors of autologous and allogeneic HCT, as well as identifies high risk groups in this population, thus setting the stage for appropriate long-term follow-up of the vulnerable sub–groups. [Display omitted] [Display omitted]

Health profiles of 996 melanoma survivors: the M. D. Anderson experience

BackgroundThe incidence and survival of melanoma are increasing, but little is known about its long-term health effects in adult survivors.MethodsA health survey was available from 996 melanoma survivors (577 treated with surgery alone, and 391 with combined treatments). Their medical/physiologic and psychosocial responses were analyzed and compared with those of the survivors from other cancers.ResultsThe melanoma survivors were 44.8 ± 12.8 years of age at diagnosis (significantly younger than the survivors of other cancers) and 63.7 ± 12.8 years at survey. Melanoma survivors were less likely to report that cancer had affected their health than survivors of other cancers (15.8% vs. 34.9%). The 577 individuals treated with surgery alone reported arthritis/osteoporosis, cataracts, and heart problems most frequently (less often than survivors of other cancers). The 391 individuals who had undergone combined treatments reported circulation problems and kidney problems generally as often as survivors of other cancers. Health problems were not associated with number of decades since diagnosis but with age at diagnosis, treatment modality, and family relationships.ConclusionWe present information from a large cohort of long-term survivors of melanoma. As a group, they were less likely to report that cancer had affected their overall health than survivors of other cancers; a number of disease related and psychosocial factors appear to influence their health profiles.

Impact of Hematopoietic Cell Transplantation with Total Body Irradiation on the Health Status of Childhood Leukemia Survivors: A Report from the Childhood Cancer Survivor Study (CCSS).

Hematopoietic cell transplantation (HCT) using total body irradiation (TBI) continues to be an important treatment for children with recurrent/high risk acute leukemias. Previous studies in children examining the impact of TBI have been limited by small numbers and short length of follow-up. This study compares global health status in a large cohort of long-term survivors after HCT for acute leukemia (cases) that received TBI and compares them to patients treated for leukemia who did not receive HCT (controls).Methods: Participants were part of the CCSS, a large multi-institutional study of over 14,000 long-term survivors of childhood cancer (diagnosed <21 yr of age and treated between 1970–1986) who had survived greater than 5 years and completed a comprehensive health status questionnaire. Self-reported outcome measures included: (1) questions assessing general health, functional status (needing help with personal cares, household activities, ability to attend school or work), and limitations of activity (inability to climb stairs or walk one block), (2) the 18 item Brief Symptom Inventory (BSI) assessing mental health, and (3) specific questions about anxiety/pain related to disease or treatment and future health concerns. Data were analyzed from 207 cases treated for leukemia (152 ALL, 55 AML) who had received HCT/TBI and compared to 3508 controls treated for leukemia (3272 ALL, 236 AML) without HCT/TBI. Sixty four percent of cases and 51% of controls were male. The majority of cases and controls were Caucasian (81% and 83%). Mean age at diagnosis was 7.8 yr (SD 5.5yr, range 0–20) for cases and 5.6 yr (SD 4.4 yr, range 0–20) for controls, with a mean age at study participation of 19.4 yr (SD 6.8 yr, range 6–38) for cases and 20.3 yr (SD 6.5yr, range 6–42) for controls.Results: In a multivariate model (adjusting for age at interview, sex, and race), HCT/TBI cases were 2.1 times (95% confidence interval [CI] 1.3–3.5) more likely to report adverse general health, functional impairments (odds ratio [OR] 3.6, 95% CI 2.4–5.6), activity limitations (OR 4.0, 95% CI 2.9–5.5), and pain related to their cancer diagnosis or treatment (OR 3.6, 95% CI 2.3–5.8). HCT/TBI cases were not more likely than controls to report adverse mental health or anxiety related to their cancer diagnosis. Participants were also asked about health concerns and HCT/TBI cases were 1.8 times (95% CI 1.1–2.9) more likely to report concerns about future health, 2.0 times (95% CI1.4–3.0) more likely to report concerns about fertility, but were not more likely to have concerns about their ability to obtain health or life insurance.Conclusion: Survivors of childhood leukemia who received HCT with TBI do not report more anxiety or adverse mental health status compared to survivors treated without HCT/TBI. They do, however, report an increased adverse perception of general health, functional impairments, activity limitations, pain, and more concerns regarding their future health and fertility. HCT survivors should have ongoing long-term follow-up and be monitored closely so that appropriate interventions may be provided.